With age-adjusted incidences of 86.2 per 100,000 person-years and overall mortality rates of ˜43%, acute lung injury (ALI) and its most severe form, the acute respiratory distress syndrome (ARDS), remain a major cause of death in intensive care (1,2). The pathological hallmarks of the disease comprise diffuse alveolo-capillary injury and an increased lung permeability associated with a strong inflammatory response (3,4). These changes underlie the clinical presentation which is characterized by an acute onset, severe hypoxemia and a proteinaceous lung oedema. Despite a multitude of large multi-centric clinical trials to explore the potential of various therapeutic strategies including the use of glucocorticoids, ketoconazole, lisofylline, alprostadil, inhaled NO or supplemented surfactant (5-7), no therapeutic pharmacological intervention could so far improve the clinical outcome of ALI/ARDS. So far, the only evident improvement for the survival of ARDS patients has been achieved by the implementation of minimal invasive ventilation strategies with low tidal volumes as compared to the previously used high tidal volumes (8).
In a recent experimental study, Imai and co-workers could demonstrate that angiotensin converting enzyme 2 (ACE2), which converts Ang II to Ang-(1-7) by cleavage of one amino acid, protects mice from severe acute lung injury induced by acid aspiration or sepsis (9). The authors attributed this finding to the fact that ACE2 will decrease Ang II concentration and thus, reduce the activation of the Ang II type I receptor (AT1). This notion has triggered a series of studies demonstrating the effectiveness of AT1 receptor blockers or ACE inhibitors for the treatment of various forms of experimental acute lung injury (10-13).
Importantly however, the cleavage product of Ang II by ACE2, Ang-(1-7), is not an inert waste product of the angiotensin-pathway, but may exert active biological functions. Ang-(1-7) binds to the G protein-coupled receptor Mas (14) which appears to be a physiological antagonist of the AT1a receptor (15), and potentially to other receptors. Binding of Ang-(1-7) to its receptor(s) may thus contribute critically to the previously demonstrated beneficial effects of interventions in the angiotensin pathway on the pathology of ALI/ARDS.
The U.S. Pat. No. 6,235,766 refers to non-peptidic agonists of Ang-(1-7) receptors, and particularly discloses 1-(p-thienylbenzyl)imidazoles having a marked action on Ang-(1-7) receptors and mimicking the biological action of the effector hormone Ang-(1-7).
The international patent application WO 2006/128266 refers to the interaction between the Mas receptor and Ang-(1-7) or its analogues in the context of controlling the functions of the reproductive system.
The international patent application WO 2007/000036 refers to the use of peptidic or non-peptidic Mas receptor agonists and antagonists as apoptotic activity modulators.
The international patent application WO 2007/121546 refers to the use of peptidic or non-peptidic Mas receptor agonists for modulating metabolic activities related to the clinical manifestation of the metabolic syndrome or its complications.
We speculated that Ang-(1-7) or related agonists may represent a new and promising strategy for the treatment of ALI/ARDS. Thus, the object of the present invention is to provide means and methods for a pharmacological intervention in the patho-physiologic events underlying ALI/ARDS.